rs140751492

Variant names:

• chr3-4362192-C-T
• rs140751492
• NM_182760.4:c.1077G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_182760.4(SUMF1):​c.1077G>A​(p.Ser359Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000522 in 1,614,192 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: SUMF1 NM_182760.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.90
• Publications: 1 publications found

Genes affected

SUMF1 (HGNC:20376): (sulfatase modifying factor 1) This gene encodes an enzyme that catalyzes the hydrolysis of sulfate esters by oxidizing a cysteine residue in the substrate sulfatase to an active site 3-oxoalanine residue, which is also known as C-alpha-formylglycine. Mutations in this gene cause multiple sulfatase deficiency, a lysosomal storage disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

SUMF1 Gene-Disease associations (from GenCC):

• mucosulfatidosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 3-4362192-C-T is Benign according to our data. Variant chr3-4362192-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 459635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.9 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00255 (388/152328) while in subpopulation AFR AF = 0.00902 (375/41570). AF 95% confidence interval is 0.00827. There are 3 homozygotes in GnomAd4. There are 170 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182760.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUMF1	NM_182760.4	MANE Select	c.1077G>A	p.Ser359Ser	synonymous	Exon 9 of 9	NP_877437.2
	SUMF1	NM_001164675.2		c.1017G>A	p.Ser339Ser	synonymous	Exon 8 of 8	NP_001158147.1	Q8NBK3-5
	SUMF1	NM_001164674.2		c.1002G>A	p.Ser334Ser	synonymous	Exon 8 of 8	NP_001158146.1	Q8NBK3-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUMF1	ENST00000272902.10	TSL:1 MANE Select	c.1077G>A	p.Ser359Ser	synonymous	Exon 9 of 9	ENSP00000272902.5	Q8NBK3-1
	SUMF1	ENST00000405420.2	TSL:1	c.1017G>A	p.Ser339Ser	synonymous	Exon 8 of 8	ENSP00000384977.2	Q8NBK3-5
	SUMF1	ENST00000948922.1		c.1098G>A	p.Ser366Ser	synonymous	Exon 9 of 9	ENSP00000618981.1

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 387 AN: 152210 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00902

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000727 AC: 181 AN: 249114 AF XY: 0.000504

Gnomad AFR exome AF: 0.00990

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000311 AC: 454 AN: 1461864 Hom.: 1 Cov.: 33 AF XY: 0.000272 AC XY: 198 AN XY: 727234

African (AFR) AF: 0.0110 AC: 368 AN: 33480

American (AMR) AF: 0.000648 AC: 29 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111990

Other (OTH) AF: 0.000646 AC: 39 AN: 60396

GnomAD4 genome AF: 0.00255 AC: 388 AN: 152328 Hom.: 3 Cov.: 33 AF XY: 0.00228 AC XY: 170 AN XY: 74490

African (AFR) AF: 0.00902 AC: 375 AN: 41570

American (AMR) AF: 0.000588 AC: 9 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00147 Hom.: 0

Bravo AF: 0.00295

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Multiple sulfatase deficiency (3)
-	-	2	not provided (2)
-	-	1	SUMF1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	4.5
DANN	Benign	0.64
PhyloP100		-3.9
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs140751492; hg19: chr3-4403876; COSMIC: COSV99794424;